A Comparative Study of Microwave-Assisted and Conventional Heating Approaches for the Multicomponent Synthesis of 4,6-Diarylpyrimidines
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Nov 21, 2023
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Abstract
A series of 2-amino-4,6-diarylpyrimidines were synthesized using a Biginelli-type three-component strategy optimized in conventional-heated reflux, in contrast to a non-conventional approach using a mono-mode microwave reactor. Conventional heating protocols involved organic solvents and general base catalysis, whereas a microwave-assisted method followed experimental protocols framed within the principles of green chemistry by using CaCl2 as a catalyst in solvent-free conditions. This study revealed that although conventional heating led to the main product in higher yields at longer reaction times, the microwave strategy suceeded in substantially shorter reaction times, with yields ranging from acceptable to good and efficiencies comparable to conventional heating methodology.
Keywords
4,6-diarylaminopyrimidines; microwave-irradiated synthesis; monomode reactor; Biginelli-type reaction.
References
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doi: 10.1016/B978-0-12-818584-1.00003-3
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doi: 10.3762/bjoc.7.107
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doi: 10.1002/1521-3773(20000915)39:18
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doi: 10.1007/s11164-011-0348-1
[22] Ravichandran S, Karthikeyan E. Microwave Synthesis - A Potential Tool for Green Chemistry. International Journal of ChemTech Research, 2011, 3(1), 466-470.
[23] Heravi MM, Ghavidel M, Heidari B. Microwave-Assisted Biginelli Reaction: An Old Reaction, a New Perspective. Current Organic Synthesis, 2016, 13, 569-600.
doi: 10.2174/1570179413666151218202307
[24] Pasunooti KK, Chai H, Jensen CN, Gorityala BK, Wang S, Liu XW. A microwave-assisted, copper-catalyzed three-component synthesis of dihydropyrimidinones under mild conditions. Tetrahedron Letters. 2011, 52, 80-84.
doi: 10.1016/j.tetlet.2010.10.150
[25] Liang B, Wang X, Wang J. X, Dua Z. New three-component cyclo- condensation reaction: microwave assisted one-pot synthesis of 5- unsubstituted-3,4-dihydropyrimidin-2(1H)-ones under solvent-free conditions, Tetrahedron. 2007, 63, 1981-1986.
doi: 10.1016/j.tet.2006.12.062
[26] Anastas P, Eghbali N. Green chemistry: Principles and practice. Chemical Society Reviews, 2010, 39, 301-312.
doi: 10.1039/B918763B
[27] Wanisa AM, Amna QA, Asma E. Green chemistry: Principles, applications and disadvantages, Chemical Methodologies, 4: 408-423, 2020.
doi: article_101213.html
[28] Chen TL, Kim H, Pan SY, Tseng PC, Lin YP, Chiang PC. Implementation of green chemistry principles in circular economy system towards sustainable development goals: Challenges and perspectives, Science of The Total Environment, 716: 136998, 2020.
doi: 10.1016/j.scitotenv.2020.136998
[29] Clark JH, English JP, Winnek, PS, Marson HW, Cole QP, Clapp JW. Studies in chemotherapy XII. Some sulphanilamidoheterocycles, Journal of the American Chemical Society, 68(1):96-99, 1946.
doi: 10.1021/ja01205a031
[30] Kangarajan V, Gopalakrishnan M. Synthesis and in vitro microbiological evaluation of an array of biolabile 2-morpholino-N-(4,6-diarylpyrimidin-2-yl)acetamides, European Journal of Medicinal Chemistry, 45(4): 1583-1589, 2010.
doi: 10.1016/j.ejmech.2009.12.068
[31] Thanh ND, Thanh-Mai NT, Synthesis of N-tetra-O-acetyl-β-D-glucopyranosyl-N´-(4,6´- diarylpyrimidin-2´-yl)thioureas. Carbohydrate Research, 344(17): 2399-2405, 2009. Journal of American Chemical Society, 124(4): 536–537, 2002.
doi: 10.1021/ja0172181
doi: 10.1016/j.carres.2009.09.002
[32] Miura K, Nakagawa T, Hosomi A, Lewis Base-Promoted Aldol Reaction of Dimethylsilyl Enolates in Aqueous Dimethylformamide: Use of Calcium Chloride as a Lewis Base Catalyst.
[33] Kulkarni PS, Calcium Chloride/HCl An Efficient Co-catalytic System For Synthesis Xanthene Under Microwave Condition, in Proceedings of the 20th International Electronic Conference on Synthetic Organic Chemistry, 1–30 November 2016, MDPI: Basel, Switzerland.
doi: 10.3390/ecsoc-20-c001
[34] Hongqiang L, Jian X, Optimization of microwave-assisted calcium chloride pretreatment of corn stover, Bioresource Technology, 127: 112-118, 2013.
doi: 10.1016/j.biortech.2012.09.114
[35] International Chemical Safety Cards (ICSCs). ICSC database.
https://www.ilo.org/dyn/icsc/showcard.display?p_version=2&p_card_id=0894
[36] Amresco. Safety Data Sheet. Guanidine Hydrochloride.
https://www.criver.com/sites/default/files/resources/doc_a/GuanidineHydrochlorideMaterialSafetyDataSheetMSDS.pdf
transcriptase, European Journal of Medicinal Chemistry, 211: 113063-113078, 2011.
doi: 10.1016/j.ejmech.2020.113063
[2] Schultz DC, Johnson RM, Ayyanathan K, Miller J, Whig K, Kamalia B, Dittmar M, Weston S, Hammond HL, Dillen C, Ardanuy J, Taylor L, Lee JS, Li M, Lee E, Shoffler C, Petucci C, Constant S, Ferrer M, Thais CA, Frieman MB, Cherry S. Pyrimidine inhibitors synergize
with nucleoside analogues to block SARS-CoV-2, Nature, 604: 134-140, 2022.
doi: 10.1038/s41586-022-04482-x
[3] Dragún M, Novotny RB, Beranek J. Antiviral activities of pyrimidine nucleoside analogues: Some structure—activity relationships, Acta Virologica, 34(4): 321-329, 1990. PMID: 1981442.
[4] Sudha-Rani K, Lakshmi-Durga J, Srilatha M, Sravani M, Sunand V, Vinod B. Synthesis, characterization, anthelmintic and in silico evaluation of 4,6-disubstituted pyrimidine-2-one derivatives, Der Pharma Chemica, 10(8): 57-61, 2018. Corpus ID: 212470803.
[5] Takagi K, Tanaka M, Morita H, Ogura K, Ishii K, Nakata N, Ozeki M. Synthesis and analgesic activity of 4-amino-1,2-dihidro-5-(2-hidroxyphenyl)-3H-pyrazol-3-ones and 5-amino-6-(2- hidroxyphenyl)pyrimidin-4(3H)-ones, European Journal of Medicinal Chemistry, 22(3):239-242, 1987.
doi: 10.1016/0223-5234(87)90055-9
[6] Bayramoglu D, Kurtay G, Güllü M. Ultrasound assisted rapid synthesis of of 2-aminopyrimidine and barbituric acid derivatives, Synthetic Communications, 50(5): 649-658,2020.
doi: 10.1080/00397911.2019.1705349
[7] Ma L, Li S, Zheng H, Chen J, Lin L, Ye X, Chen Z, Xu Q, Chen T, Yang J, Qiu N, Wang G, Peng A, Ding Y, Wei Y, Chen L. Synthesis and biological activity of novel barbituric acid and thiobarbituric acid derivatives against non-alcoholic fatty liver disease, European
Journal of Medicinal Chemistry, 46(6): 2003-2010, 2011.
doi: 10.1016/j.ejmech.2011.02.033
[8] Löffler M, Carrey EA, Zameitat E. New perspectives on the roles of pyrimidines in the central nervous system, Nucleosides, nucleotides and nucleic acids, 37(5): 290-306, 2018.
doi: 10.1080/15257770.2018.1453076
[9] Sharma V, Chitranshi N, Agarwal AK. Significance and biological importance of pyrimidine in the microbial world, International Journal of Medicinal Chemistry, 2014: 202784, 2014. PMID: 25383216.
doi: 10.1155%2F2014%2F202784
[10] Pathak V, Maurya H, Sharma S, Srivastava KK, Gupta A. Synthesis and biological evaluation of substituted 4,6-diarylpyrimidines and 3,5-diphenyl-4,5-dihydro-1H-pyrazoles as antitubercular agents, Bioorganic & Medicinal Chemistry Letters, 13(1): 2892-2896, 2014.
doi: 10.1016/j.bmcl.2014.04.094.
[11] Orozco-Lopez F, Guerrero-Villalobos LR, Cuervo-Prado PA. Computer-aided design, synthesis and characterization of molecular hybrids of dihydropyrazoles, aminopyrimidines, and thiazolidin-4-ones as potential inhibitors of the penicillin-binding protein 3 (PBP-3) of Escherichia coli. Universitas Scientiarum, 26(1): 17-35.
doi: 10.11144/Javeriana.SC26-1.cads
[12] Chiacchio MA, Iannazzo D, Romeo R, Giofré SV, Legnani L. Pyridine and pyrimidine derivatives as privileged scaffolds in biologically active agents, Current Medicinal Chemistry, 26(40): 7166-7195, 2019. doi: 10.2174/0929867325666180904125400
[13] Dinastiya EM, Verbitskiy EV, Gadirov RM, Samsonova LG, Degtyarenko KM, Grigoryev DV, Kurtcevich AE, Solodova TA, Tel´minov EN, Rusinov GL, Chupakhin ON, Charushin VN. Investigation of 4,6-di(hetero)aryl-substituted pyrimidines as emitters for non-doped
OLED and laser dyes, Journal of Photochemistry and Photobiology A: Chemistry, 408(1):113089, 2021.
doi: 10.1016/j.jphotochem.2020.113089
[14] Fatahala SS. Retrosynthesis analysis; a way to design a retrosynthesis map for pyridine and pyrimidine ring. Annals of Advances in Chemistry, 1(1): 57-60, 2017.
doi: 10.29328/journal.aac.1001007
[15] Kappe CO. A reexamination of the mechanism of the Biginelli dihydropyrimidine synthesis. Support for an N-acyliminium ion intermediate. Journal of Organic Chemistry, 62(21):7201-7204, 1997.
doi: 10.1021/jo971010u
[16] Biginelli P, Über Aldehyduramide des Acetessigäthers. Berichte der deutschen chemischen Gesselschaft, 24(1): 1317-1319, 1891.
doi: 10.1002/cber.189102401228
[17] Heravi M, Zadsirjan V, Recent Advances in Applications of Name Reactions in Multicomponent Reactions - Chapter 3, Elsevier, 2020, 139-268.
doi: 10.1016/B978-0-12-818584-1.00003-3
[18] Müller TJJ, Multicomponent reactions. Beilstein Journal of Organic Chemistry,2011, 7, 960–961,
doi: 10.3762/bjoc.7.107
[19] Dömling A, Ugi I, Multicomponent Reactions with Isocyanides. Angewandte Chemie International Edition, 2000, 39, 3168.
doi: 10.1002/1521-3773(20000915)39:18
[20] Dömling A, Multicomponent Reactions - Superior Chemistry Technology For The New Millennium. Organic Chemistry Highlights, 2004, April 5.
doi: 2005/05April.shtm
[21] Bassyouni F, Abu-Bakr S, Rehim M. A. Evolution of microwave irradiation and its application in green chemistry and biosciences. Research on Chemical Intermediates, 2012, 38, 283–322.
doi: 10.1007/s11164-011-0348-1
[22] Ravichandran S, Karthikeyan E. Microwave Synthesis - A Potential Tool for Green Chemistry. International Journal of ChemTech Research, 2011, 3(1), 466-470.
[23] Heravi MM, Ghavidel M, Heidari B. Microwave-Assisted Biginelli Reaction: An Old Reaction, a New Perspective. Current Organic Synthesis, 2016, 13, 569-600.
doi: 10.2174/1570179413666151218202307
[24] Pasunooti KK, Chai H, Jensen CN, Gorityala BK, Wang S, Liu XW. A microwave-assisted, copper-catalyzed three-component synthesis of dihydropyrimidinones under mild conditions. Tetrahedron Letters. 2011, 52, 80-84.
doi: 10.1016/j.tetlet.2010.10.150
[25] Liang B, Wang X, Wang J. X, Dua Z. New three-component cyclo- condensation reaction: microwave assisted one-pot synthesis of 5- unsubstituted-3,4-dihydropyrimidin-2(1H)-ones under solvent-free conditions, Tetrahedron. 2007, 63, 1981-1986.
doi: 10.1016/j.tet.2006.12.062
[26] Anastas P, Eghbali N. Green chemistry: Principles and practice. Chemical Society Reviews, 2010, 39, 301-312.
doi: 10.1039/B918763B
[27] Wanisa AM, Amna QA, Asma E. Green chemistry: Principles, applications and disadvantages, Chemical Methodologies, 4: 408-423, 2020.
doi: article_101213.html
[28] Chen TL, Kim H, Pan SY, Tseng PC, Lin YP, Chiang PC. Implementation of green chemistry principles in circular economy system towards sustainable development goals: Challenges and perspectives, Science of The Total Environment, 716: 136998, 2020.
doi: 10.1016/j.scitotenv.2020.136998
[29] Clark JH, English JP, Winnek, PS, Marson HW, Cole QP, Clapp JW. Studies in chemotherapy XII. Some sulphanilamidoheterocycles, Journal of the American Chemical Society, 68(1):96-99, 1946.
doi: 10.1021/ja01205a031
[30] Kangarajan V, Gopalakrishnan M. Synthesis and in vitro microbiological evaluation of an array of biolabile 2-morpholino-N-(4,6-diarylpyrimidin-2-yl)acetamides, European Journal of Medicinal Chemistry, 45(4): 1583-1589, 2010.
doi: 10.1016/j.ejmech.2009.12.068
[31] Thanh ND, Thanh-Mai NT, Synthesis of N-tetra-O-acetyl-β-D-glucopyranosyl-N´-(4,6´- diarylpyrimidin-2´-yl)thioureas. Carbohydrate Research, 344(17): 2399-2405, 2009. Journal of American Chemical Society, 124(4): 536–537, 2002.
doi: 10.1021/ja0172181
doi: 10.1016/j.carres.2009.09.002
[32] Miura K, Nakagawa T, Hosomi A, Lewis Base-Promoted Aldol Reaction of Dimethylsilyl Enolates in Aqueous Dimethylformamide: Use of Calcium Chloride as a Lewis Base Catalyst.
[33] Kulkarni PS, Calcium Chloride/HCl An Efficient Co-catalytic System For Synthesis Xanthene Under Microwave Condition, in Proceedings of the 20th International Electronic Conference on Synthetic Organic Chemistry, 1–30 November 2016, MDPI: Basel, Switzerland.
doi: 10.3390/ecsoc-20-c001
[34] Hongqiang L, Jian X, Optimization of microwave-assisted calcium chloride pretreatment of corn stover, Bioresource Technology, 127: 112-118, 2013.
doi: 10.1016/j.biortech.2012.09.114
[35] International Chemical Safety Cards (ICSCs). ICSC database.
https://www.ilo.org/dyn/icsc/showcard.display?p_version=2&p_card_id=0894
[36] Amresco. Safety Data Sheet. Guanidine Hydrochloride.
https://www.criver.com/sites/default/files/resources/doc_a/GuanidineHydrochlorideMaterialSafetyDataSheetMSDS.pdf
How to Cite
Becerra-Rivas, C. A., Cuervo-Prado, P. A., & Orozco-Lopez, F. (2023). A Comparative Study of Microwave-Assisted and Conventional Heating Approaches for the Multicomponent Synthesis of 4,6-Diarylpyrimidines. Universitas Scientiarum, 28(3), 300–315. https://doi.org/10.11144/Javeriana.SC283.acso
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Química Orgánica / Organic Chemistry / Química Orgânica
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